Challenges in the Design, Development, Manufacturing, and Testing of Transdermal Drug Delivery Systems – The Third Largest Global Drug Administration Route

Transdermal drug delivery technology, as an important branch of the field of drug delivery, provides a non-invasive therapeutic approach that can reduce drug side effects, improve patient compliance, and allow for sustained or controlled drug release.

In recent years, transdermal formulation technology has witnessed significant advancements. The global market size for transdermal formulations continues to expand, with projections indicating it will reach USD 10.67 billion by 2026. The Chinese market is also demonstrating strong growth momentum, with its market size expected to rise to RMB 10.49 billion by 2024.

However, despite the significant market potential of transdermal drug delivery technology, it faces challenges such as high technical barriers, the lack of unified standards for evaluation systems, and a scarcity of talent. Moreover, the high entry threshold for transdermal formulations severely tests a company’s supply chain integration capabilities and innovation capacity.

Recently,China Pharmaceutical Full Industry Chain New Resources ConferenceSuccessfully held in Nanjing, the special session of the Conference on R&D and Innovative Application Collaboration in Transdermal Technology featured in-depth presentations and peer exchanges by industry experts. Among them, they"Design, Development, Production, and Testing of Transdermal Drug Delivery Systems"This topic was the subject of an in-depth roundtable discussion.They are Li Feifei, Founder of Beijing Beimei Pharmaceutical Co., Ltd.; Wang Yuan, General Manager of Pharmablock Chemicals (Shanghai) Inc.; Wang Zhengzheng, General Manager of Beijing Xinyi Huida Electromechanical Equipment Co., Ltd.; Dong Shan from Shandong Xinsheng Times New Materials Co., Ltd.; and Tang Hongmin, General Manager of Beijing Hebang Xingye Scientific Instrument Co., Ltd.

Beimei Pharmaceutical, Li Feifei:This roundtable discussion covers all aspects of transdermal drug delivery, from design, development, and manufacturing to testing. The guests invited today are leading experts representing each of these stages. Everyone is familiar with the classification of topical formulations, which are generally categorized into local-acting medications and transdermal patches. What problems or technical barriers arise during the development process, depending on different mechanisms of action or formulation technologies? First, let us invite Mr. Wang Yuan to share his experiences in developing topical formulations over the years and to discuss the current challenges he faces.

Yaoyuan Pharmaceutical, Wang Yuan:Yaoyuan Pharmaceuticals primarily focuses on CDMO services for new drug development. In the field of topical medications, our company is more frequently engaged with innovative drugs for local administration. Compared to other innovative drugs, topical semi-solid formulations are relatively unique and somewhat more complex.

The complexity is mainly reflected in several aspects. First, the required dosage form must be designed according to different molecules; for example, whether a drug is formulated as an ointment or a gel depends not only on the indication but also on the inherent properties of the molecule itself. The choice of dosage form is determined by the selected excipients, which can significantly impact drug stability.

This necessitates starting with a thorough understanding of the properties of the Active Pharmaceutical Ingredient (API). From initial information and planning—ranging from the intended indications for the molecule in its early stages, through preliminary pharmacodynamic preclinical studies, to its eventual development into a drug that achieves the desired therapeutic effects—there are numerous translational processes involved. This journey requires multidisciplinary collaboration, including interactive evaluation of pharmacodynamic models, to identify the most promising development path. Building on this selected direction, further pharmaceutical research, development, and optimization are conducted to finalize the formulation and optimize the manufacturing process. These represent the key challenges in developing innovative topical semi-solid dosage forms.

Beimei Pharmaceutical, Li Feifei:Mr. Wang Yuan has extensive experience in innovative drug development, where the design of topical formulations may present additional challenges. Unlike oral and injectable systemic therapies, which deliver 100% of the administered dose into the body, topical formulations are more complex because the vehicle (base) can influence the delivery process, affect stability, and impact therapeutic efficacy.

Yaoyuan Pharmaceutical, Wang Yuan:Indeed, because the manufacturing steps appear relatively simple—typically involving heating, stirring/homogenization, cooling, and other processes following pretreatment. Why are semi-solid preparations considered complex formulations? Because such formulations present certain challenges in terms of chemical properties, physical properties, and microstructure; itCompared with solid dosage forms, semi-solids exhibit a certain degree of fluidity and relatively faster molecular motion, posing greater stability challenges for chemically unstable molecules.For instance, many excipients contain trace amounts of oxidative impurities, and antioxidants may be required in the formulation to counteract their oxidative effects. Since research on excipients is not always comprehensive, they may potentially exert chemical effects on our drug product.

From a physical standpoint, semi-solid formulations must exhibit uniform characteristics. They may be either solution-based or suspension-based and are required to maintain a stable state throughout the drug’s lifecycle or within the clinically defined period. It is unacceptable for the initial drug concentration to meet specifications while subsequent crystallization leads to subtherapeutic levels. There have been cases abroad where products were withdrawn from the market due to such issues.

Beimei Pharmaceutical, Li Feifei:Quality by Design (QbD) is frequently employed in pharmaceutical formulation development, as quality is indeed built into the design. The characteristics of the active pharmaceutical ingredient (API) are taken into consideration from the initial design stage. Excipients also play a significant role during the formulation process; however, we currently do not conduct in-depth investigations into their characteristic parameters when selecting excipients. In fact, for topical formulations, excipient characteristic parameters have an even greater impact on the final product. Changes in viscosity of polymeric excipients during storage—such as chain degradation or further polymerization—can have substantial effects that directly influence the ability to produce formulations with consistent quality.

We have invited Mr. Dong Shan, a representative from the excipient industry, to share his insights. Mr. Dong primarily specializes in hot-melt adhesive-based excipients. What developments or progress has his company made to date?

New Era of Health, Dong Shan:The excipients produced by Xinsheng Shidai are based on styrene-isoprene-styrene (SIS) block copolymers, which are widely used in both conventional hot-melt patches for generic chemical drugs and traditional Chinese medicine plasters. SIS exhibits excellent melt stability and melt processability, conferring significant advantages in patch formulation.In China, three companies have already filed their products for recordation, with Xinsheng Shidai being the only domestic manufacturer.In China,New Sheng's production capacity is relatively large, fully capable of meeting domestic demand for excipients.

We maintain relatively stringent standards for pricing, supply lead times, and quality control. We are pursuing the path of domestic substitution for pharmaceutical excipients and offer a high degree of customer collaboration, which constitutes a competitive advantage over foreign enterprises. I am confident that the domestic excipients industry in China holds significant promise under future economic and policy conditions.

Beimei Pharmaceutical, Li Feifei:I was also deeply involved in the regulatory filing of the excipients for Dong Zong’s company, New Sheng Era, where I conducted quality control and optimization based on formulation requirements during the quality research process.

As Mr. Wang Yuan just mentioned, impurities related to excipients should also be monitored during the development process, as their presence may impact product quality and safety. The decision to file for domestic SIS registration was based on a point raised by Mr. Dong: Chinese manufacturers, by securing backend market supply and controlling costs, can provide greater assurance for the development of China’s transdermal formulation industry.

Production equipment is also a key link in industrialization.Mr. Wang Zhengzheng’s company, Xinyi Huida, primarily focuses on the development of equipment for transdermal patches, which has provided substantial support to our R&D and production efforts. Previously, when transdermal patches were mentioned, people would typically think of products approved by Japan or the U.S. FDA, as well as equipment from Japan, Europe, and the United States. However, after more than two decades of continuous investment and development, Xinyi Huida’s R&D and manufacturing equipment are now capable of producing products that meet regulatory approval requirements. Mr. Wang will now provide further details.

Xinyi Huida, Wang Zhengzheng:Dear Colleagues,Xinyi Huida has always focused on the production and R&D of equipment for topical patch formulations,Our company can provide extensive data to facilitate equipment optimization during the production process. In 2001, Mr. Lin Weihua of Xinyi Huida participated in the research, development, and manufacturing of China’s first gel coating machine. To date,Our gel coating machines are highly mature, ranging from laboratory-scale coaters and mixers to pilot-scale and large-scale production systems for coating and mixing. This includes pre-mixing and automated CIP (Clean-in-Place) cleaning, all of which are well-established.From an equipment perspective, our precision can be controlled to 3%-5%, and hot melt adhesive can be controlled to 2%-5%.

Beimei Pharmaceutical, Li Feifei:We have consistently called on everyone to recognize that the optimization of equipment and the development of auxiliary materials rely heavily on feedback from practical applications. Domestically produced materials and equipment offer significant advantages in terms of cost and supply lead times. With broader adoption and more specific requirements from users, the industry’s supply chain and development will no longer lag behind international standards.

Beimei Pharmaceutical, Li Feifei:We have always described quality control or analysis as our “eyes.” The establishment of quality standards and the setting of critical quality parameters are of paramount importance, which are inextricably linked to testing equipment.

I have always stated that Mr. Tang Hongmin of Hebang Xingye is not merely an instrument provider, but a researcher. We have collaborated for many years on the development and standardization of transdermal detection methods, as well as the refinement of various modules. Mr. Tang has been deeply engaged in this field and has launched equipment developed through several years of dedicated effort.

Hebang Xingye, Tang Hongmin:Thank you all. Mr. Wang Yuan aims to achieve clinical objectives by leveraging the inherent properties of the active pharmaceutical ingredient (API) alongside modifications in pharmaceutical excipients and formulation. My academic background is in analytical chemistry, and I have spent 15 years working for an instrumentation company, consistently developing instruments from the perspective of pharmaceutical researchers. For transdermal delivery systems, it is essential to begin with in vitro pharmaceutical studies, primarily focusing on drug release and permeation, followed by in vivo bioequivalence (BE) studies, including Phase II and Phase III clinical trials—all of which rely heavily on analytical methods. Since the API is an oily compound, it imposes stringent requirements on release conditions. In designing this testing instrument, considerations such as whether to employ full or partial sampling, and how to optimize the approach for such lipophilic compounds, can significantly reduce the difficulty of detection. If the detection process itself is straightforward, another issue must be addressed: whether the medium might back-permeate, and whether its fluidity could disrupt the microstructure. In such cases, the resulting data may not accurately reflect the true morphological and microstructural characteristics.

Permeation is the same,Hebang Xingye has now launched a porcine skin product. Given the significant research challenges involved, the company has undertaken the national standardization research for porcine skin. After approximately one year of research, substantial breakthroughs have recently been achieved.Currently, the company’s independently developed instruments, such as transdermal diffusion cells and transepidermal water loss (TEWL) meters, also incorporate the principles of in vitro pharmaceutical release and permeation.

In the field of transdermal formulations, to address the issue of bioequivalence evaluation, we have introduced the latest technology, which is also under investigation by the FDA, namely the implantation of probes into the subcutaneous tissue.Therefore, taken as a whole, this is a comprehensive solution, and we hope it proves helpful to everyone.

Beimei Pharmaceutical: Li FeifeiMany colleagues who have conducted transdermal permeation tests are well aware of the substantial differences between ex vivo and in vivo skin. Even with optimal preservation of ex vivo samples, such as using freshly shaved pig skin purchased specifically for the purpose, significant changes in skin properties occur due to prolonged immersion during experiments. This makes it difficult to evaluate the in vitro–in vivo correlation (IVIVC) of pharmaceutical products. I have long anticipated the introduction of equipment designed for in vivo transdermal testing.

Hebang Xingye, Tang Hongmin:Skin undergoes significant changes immediately after being excised from a living body, compounded by the effects of hydration. Currently, the industry has not yet identified all relevant skin indicators. However, we have identified several key markers that exhibit strong correlations. Critical factors to consider during development include the duration of ex vivo storage, as subcutaneous lymphocytes and tissue fluid demonstrate high viability, and subcutaneous targets are abundant.

Beimei Pharmaceutical, Li Feifei:Human clinical trials invariably involve a certain degree of variability. Even under the most rigorous experimental conditions, studies conducted on porcine skin exhibit substantial variability. Therefore, the development, statistical analysis, and evaluation of transdermal methods are critical. The industry is currently exploring the use of local pharmacokinetics to assess the subcutaneous distribution and metabolism of topically acting drugs, with these emerging technologies continuing to evolve.

In fact, many issues are more frequently raised during the product design and R&D stages. We put forward numerous new requirements for excipients, process equipment, and testing equipment, which necessitates strong support from our partners across the upstream and downstream supply chains. Let us work together to promote the development of this industry.